Oleoylethanolamide ameliorates collagen-induced rheumatoid arthritis via activation of GPR119

Lower levels of oleoylethanolamide (OEA) have been observed in the synovial fluids of patients with rheumatoid arthritis and osteoarthritis compared to healthy controls. OEA is known as an anti-inflammatory lipid and acts as an endogenous ligand for GPR119. This study investigated the functional roles of GPR119 using a murine collagen-induced arthritis (CIA) model. The effects of OEA and AR231453, a selective synthetic GPR119 agonist, were tested on the CIA model in Gpr119 wild-type (WT) and deficient DBA-1 J mice. In the CIA model, administration of OEA or AR231453 reduced arthritis scores, foot thickness, loss of proteoglycan, and bone erosion in Gpr119 WT mice, but not in Gpr119-deficient mice. Treatment with OEA or AR231453 significantly suppressed the CIA-induced increase in pro-inflammatory cytokine expression in the feet and IgG levels in the serum, and rebalanced Th1/Th17 and Treg cells in the spleens of Gpr119 WT mice, but not in Gpr119-deficient mice. Additionally, OEA and AR231453 suppressed mRNA expression levels of inflammatory cytokines in human SW982 synovial cells. Both compounds also suppressed Th1/17 cell differentiation and enhanced Treg differentiation in splenocytes from Gpr119 WT mice, but not in Gpr119 knockout mice. These findings suggest that GPR119 activation may serve as a therapeutic strategy for rheumatoid arthritis by regulating Th1/Th17/Treg cell differentiation and rebalancing Th1/Th17 and Treg cells.